FLAVIVIRUSES 1103 Background and Classification 1103 Structure and Physical Properties of the Virion 1104 Binding and Entry 1105 Genome Structure 1106 Translation and Proteolytic Processing 1107 Features of the Structural Proteins 1108 Features of the Nonstructural Proteins 1109 RNA Replication 1112 Membrane Reorganization and the Compartmentalization of Flavivirus Replication 1112 Assembly and Release of Particles from Flavivirus-infected Cells 1112 Host Resistance to Flavivirus Infection 1113

Flaviviridae :T he Viruses and Their Replication

Summary: Much remains to be learned about the pathogenesis of the different manifestations of dengue virus (DENV) infections in humans. They may range from subclinical infection to dengue fever, dengue hemorrhagic fever (DHF), and eventually dengue shock syndrome (DSS). As both cell tropism and tissue tropism of DENV are considered major determinants in the pathogenesis of dengue, there is a critical need for adequate tropism assays, animal models, and human autopsy data. More than 50 years of research on dengue has resulted in a host of literature, which strongly suggests that the pathogenesis of DHF and DSS involves viral virulence factors and detrimental host responses, collectively resulting in abnormal hemostasis and increased vascular permeability. Differential targeting of specific vascular beds is likely to trigger the localized vascular hyperpermeability underlying DSS. A personalized approach to the study of pathogenesis will elucidate the basis of individual risk for development of DHF and DSS as well as identify the genetic and environmental bases for differences in risk for development of severe disease.

Dengue Virus Pathogenesis: an Integrated View

Publisher Summary This chapter summarizes the current understanding of the molecular biology of flaviviruses and points out promising avenues for future work. The molecular biology of flaviviruses is best understood in the context of the viral life cycle, which provides a framework for the organization of this chapter. Flavivirus particles bind to cells via interactions between the viral surface glycoprotein and cellular receptors. Several cell surface proteins have been described as putative receptors. In addition, opsonization with immunoglobulins enhances virus particle binding and infection of cells expressing immunoglobulin Fc receptors. Virions are internalized into clathrin-coated pits via receptor-mediated endocytosis. It is thought that virions are brought into a prelysosomal endocytic compartment where low pH induces fusion among the viruses and host cell membranes to release the virus nucleocapsid. The viral genome is released into the host cytoplasm by the process of nucleocapsid uncoating, which is not yet fully understood. Translation of the viral genome produces proteins that lead to replication of the viral genome and assembly of new virus particles. Flavivirus infection induces rearrangement of cytoplasmic membranes in the perinuclear region. Virus particles are thought to assemble by budding into the endoplasmic reticulum. A few studies have shown evidence for budding at the plasma membrane. Based on trans-complementation studies, it appears that genome packaging is coupled to RNA replication. Nascent virus particles pass through the host secretory pathway, where virion maturation occurs, and are released.

Molecular biology of flaviviruses.

https://espace.library.uq.edu.au/view/UQ:295107/UQ295107OA.pdf

The flavivirus NS1 protein: molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker.

Human cytomegalovirus (HCMV) is capable of manifesting disease in nearly every organ system in immunocompromised patients. This broad pathogenic tropism correlates with the ability of the virus to infect all tested vertebrate cell types in vitro, a characteristic that has made receptor identification extremely difficult. During virus entry, HCMV induces cellular morphological changes and signaling cascades consistent with engagement of cellular integrins; however, HCMV structural proteins do not possess the widely used RGD integrin-binding motif. We identified an integrin-binding disintegrin-like domain within HCMV envelope glycoprotein B, a protein required for virus entry and fusion throughout the Herpesviridae. Accepted receptor criteria are met through the use of function-blocking integrin Abs, β1 integrin knockout mouse fibroblasts, and glycoprotein B disintegrin-like peptides, all of which support a critical role for α2β1, α6β1, and αVβ3 integrins as HCMV entry receptors and signaling mediators acting during the penetration stage of the entry pathway. Strikingly, the glycoprotein B disintegrin-like domain is conserved in many human and animal herpesviruses, suggesting that integrins may support entry across this medically important virus family.

https://www.pnas.org/content/pnas/101/43/15470.full.pdf

Cellular integrins function as entry receptors for human cytomegalovirus via a highly conserved disintegrin-like domain

Dengue virus infection causes life-threatening hemorrhagic fever. Increasing evidence implies that dengue viral nonstructural protein 1 (NS1) exhibits a tendency to elicit potentially hazardous autoantibodies, which show a wide spectrum of specificity against extracellular matrix and platelet antigens. How NS1 elicits autoantibodies remains unclear. To address the hypothesis that NS1 and matrix proteins may have structural and functional similarity, cell-matrix and cell-NS1 interactions were evaluated using a cell-adhesion assay. The present study showed that dengue NS1 immobilized on coverslips resulted in more cell adhesion than did the control proteins. This cell adhesion was inhibited by peptides containing arginine-glycine-aspartic acid (RGD), a motif important for integrin-mediated cell adhesion. In addition, anti-NS1 antibodies blocked RGD-mediated cell adhesion. Although there is no RGD motif in the NS1 protein sequence, these data indicate that RGD structural mimicry exists within the NS1 antigen.

Facilitation of Cell Adhesion by Immobilized Dengue Viral Nonstructural Protein 1 (NS1): Arginine-Glycine-Aspartic Acid Structural Mimicry within the Dengue Viral NS1 Antigen

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Facilitation of Cell Adhesion by Immobilized Dengue Viral Nonstructural Protein 1 (NS1): Arginine-Glycine-Aspartic Acid Structural Mimicry within the Dengue Viral NS1 Antigen